Apart from surgery, there have been only two general approaches to tumor therapy which have been major viable alternatives in the past two decades. Although these approaches are far from perfect, sufficiently acceptable results have been obtained that, despite considerable problems with side effects and unpredictability of efficacy, these methods are, in fact, utilized in the treatment of patients.
These two approaches are, of course, chemotherapy and radiation treatment. In chemotherapy, the subject is treated with a suitable pharmaceutical substance in protocols which generally do not differ markedly from administration of other drugs. The tumor selectivity of the drug is an inherent function of its chemical nature, and most such drugs are chosen because they selectively interfere with rapidly growing cells. The radiation-centered approach can also be aided by administration of chemical substances to enhance the effectiveness of the treatment, i.e., radiosensitizers. This is particularly important for treatment of solid tumors using radiation, since the lethal power of radiation is diminished by the hypoxic nature of most tumors. Hypoxia, in general, renders cell masses relatively resistant to radiation, and thus a mechanism for overcoming this resistance may be supplied in the form of radiosensitizers which, possibly, substitute for oxygen in sensitizing the cells to the effects of the radiation.
The number of compounds which have been used as chemotherapeutic agents is large, and many of the compounds utilized are unrelated to those of the present invention. Those most closely related to the invention herein include the complexes of platinum II of square planar configuration, and, in particular, the cis-isomeric forms. As early as 1969, cis-platin (cis[PtCl.sub.2 (NH.sub.3).sub.2 ]) was shown to have antineoplastic activity. This compound is now widely used in clinics, with second generation compounds in clinical trials since 1979. It has also been possible to substitute other metals such as ruthenium and palladium for platinum as the center ion of the complex, and alternative ligands to the chloride and amino groups, such as DMSO, ethylenediamine, and so forth, have been studied (Farrell, N. P., et al, Biochem Pharmacol (1984) 33:961-973). The conventional wisdom as stated in the Farrell paper and elsewhere (Rosenberg, B., in "Cisplatin: Current Status and New Developments" (1980) Prestayko, A. W., et al, eds, Academic Press, pp. 9 et seq.; Rosenberg, B., Interdisciplinary Science Reviews (1978) 3:1-29; Roberts, J. J., in Metal Ions in Genetic Information Transfer (1981) Elsevier, pp. 273 et seq.), is that the cis-isomer is required for antitumor activity.
With regard to radiosensitizing compounds, a number of mono-nitroimidazole and mono-nitrothiazole derivatives have been shown to exhibit this activity. For example, metronidazole (METRO), misonidazole (MISO), and certain proprietary compounds such as SR-2508 (etanidazole) have been shown to have beneficial effects in sensitizing cells to radiation treatment in clinical trials (Overgaard, J., et al, in Proc 3rd Int Meeting on Prog Radio Onc, Raven Press, New York (1986)). METRO and MISO have been studied extensively, and MISO is commonly used as a standard in in vivo and in vitro tests for radiosensitizing activity (Asquith et al, Radiation Res (1974) 60:108-118; Hull et al, Brit J Cancer (1978) 37:567-569; Brown et al, Radiation Res (1980) 82:171-190; U.S. Pat. No. 4,371-540).
Because these compounds are toxic in the amounts needed to be administered in order for the effect to be exhibited, it has been attempted to utilize metals known to bind to DNA to carry the organic radiosensitizer to the target. Exemplary reports of this approach include Farrell, N. P., et al, Radiation Research (1982) 91:378-379; Bales, J. R., et al, Brit J Cancer (1982) 46:701-705; Bales, J. R., et al, J Chem Soc Chem Comm (1983) 432-433; Chibber, R., et al, Int J Radiation Oncol Biol Phys (1984) 1213-1215; Teicher, D. A., et al, ibid (1984) 11:937-941; Skov, K. A., et al, Proc 7th Intl Cong Radiation Research (Amsterdam); Broerse, J. J., et al, eds., Abstract B6-29, Martinus Nijhoff (1983), The Hague; Farrell, N. P., et al, Inorg Chim Acta (1984) 92:61-66; Chan, P. K. L., Int J Radiation Oncol Biol Phys (1986) 12:1059-1062. All of these reports are directed to radiosensitization studies using metal complexes with known radiosensitizers in complexes which are bivalent for the radiosensitizing material. In addition, the sensitization of hypoxic cells to radiation as effected by complexes of platinum and related metals with no sensitizing ligand (e.g. Douple, E. B., et al, Brit J Cancer Suppl III (1978) 37:98-102) is being exploited clinically. Nias, A. H. W., Int J Radiation Biol (1985) 48:297-314, has presented a review of the various approaches to this problem.
The Teicher et al article is particularly relevant because it discloses, among several platinum-containing complexes bisubstituted with radiosensitizers, the mono-substituted platinum complex of 1,2-diamino-4-nitrobenzene as a bidentate complex. This compound, designated "Plato" by Teicher, showed a high capacity for killing of hypoxic cells and less toxicity toward oxygenated cells. In addition, British patent application 2,093,451A and 2,122,194A disclose metal complexes of nitro-substituted pyrazoles, nitrazoles, imidazoles, and isothiazoles. These compounds are claimed to be useful in the therapy of cancer and to have antibacterial activity.
The history of cancer treatment using either direct chemotherapy or radiation with sensitization by compounds of appropriate electron affinity, such as misonidazole, shows that there is a high variability between individuals and individual tumors with regard to the sensitivity to particular reagents. That is, it seems to be unpredictable in advance what protocols, what sensitizing agents, and what chemotherapeutic agents, if any, will work in an individual instance. Some tumors appear to be easily permanently destroyed by radiation, while other are resistant. Certain tumors are responsive to, for example, cytoxan or prednisone, while others are not. A similar situation is expected to exist with regard to the heavy metal complexes containing organic ligands which are toxic to tumors or are radiosensitizers. For example, cisplatin has proven useful in the treatment of testicular cancer, but less so in treatment of cancers at other sites.
Therefore, it becomes crucial to have available a large repertoire of possibilities so that the probability that a given subject will respond to at least one or two members of the repertoire will be maximized. The present invention makes a contribution to this repertoire by adding a series of compounds which have been heretofore unavailable, and which have been shown to be effective in radiosensitizing hypoxic cells, including tumors, in model systems, as well as to have tumor toxicity in vivo even in the absence of radiation.